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Body size and risk of colorectal cancer molecular defined subtypes and pathways: Mendelian randomization analyses.

About this Publication
Title
Body size and risk of colorectal cancer molecular defined subtypes and pathways: Mendelian randomization analyses.
Pubmed ID
38350331 (View this publication on the PubMed website)
Digital Object Identifier
Publication
EBioMedicine. 2024 Feb 12; Volume 101: Pages 105010
Authors
Papadimitriou N, Qu C, Harrison TA, Bever AM, Martin RM, Tsilidis KK, Newcomb PA, Thibodeau SN, Newton CC, Um CY, Obón-Santacana M, Moreno V, Brenner H, Mandic M, Chang-Claude J, Hoffmeister M, Pellatt AJ, Schoen RE, Harlid S, Ogino S, ...show more Ugai T, Buchanan DD, Lynch BM, Gruber SB, Cao Y, Hsu L, Huyghe JR, Lin Y, Steinfelder RS, Sun W, Van Guelpen B, Zaidi SH, Toland AE, Berndt SI, Huang WY, Aglago EK, Drew DA, French AJ, Georgeson P, Giannakis M, Hullar M, Nowak JA, Thomas CE, Le Marchand L, Cheng I, Gallinger S, Jenkins MA, Gunter MJ, Campbell PT, Peters U, Song M, Phipps AI, Murphy N
Affiliations
  • Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France. Electronic address: papadimitrioun@iarc.who.int.
  • Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
  • Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA, USA.
  • MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; Bristol Medical School, Department of Population Health Sciences, University of Bristol, Bristol, UK; National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Bristol, UK.
  • Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
  • Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; School of Public Health, University of Washington, Seattle, WA, USA.
  • Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
  • Department of Population Science, American Cancer Society, Atlanta, GA, USA.
  • Unit of Biomarkers and Suceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Barcelona 08908, Spain; ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Spain; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid 28029, Spain.
  • Unit of Biomarkers and Suceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Barcelona 08908, Spain; ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Spain; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid 28029, Spain; Department of Clinical Sciences, Faculty of Medicine and Health Sciences and Universitat de Barcelona Institute of Complex Systems (UBICS), University of Barcelona (UB), L'Hospitalet de Llobregat, Barcelona 08908, Spain.
...show more
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany.
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany.
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX, USA.
  • Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
  • Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
  • Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Cancer Immunology Program, Dana-Farber Harvard Cancer Center, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria 3010, Australia; Genetic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia.
  • Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia.
  • Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA.
  • Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA; Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO, USA; Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
  • Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Biostatistics, University of Washington, Seattle, WA, USA.
  • Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden; Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden.
  • Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
  • Departments of Cancer Biology and Genetics and Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
  • Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria 3010, Australia.
  • Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • University of Hawaii Cancer Center, Honolulu, HI, USA.
  • Department of Epidemiology and Biostatistics, University of California-San Francisco, San Francisco, CA, USA.
  • Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
  • Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia.
  • Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
  • Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA.
  • Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
  • Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France.
Abstract

BACKGROUND: Obesity has been positively associated with most molecular subtypes of colorectal cancer (CRC); however, the magnitude and the causality of these associations is uncertain.

METHODS: We used Mendelian randomization (MR) to examine potential causal relationships between body size traits (body mass index [BMI], waist circumference, and body fat percentage) with risks of Jass classification types and individual subtypes of CRC (microsatellite instability [MSI] status, CpG island methylator phenotype [CIMP] status, BRAF and KRAS mutations). Summary data on tumour markers were obtained from two genetic consortia (CCFR, GECCO).

FINDINGS: A 1-standard deviation (SD:5.1 kg/m2) increment in BMI levels was found to increase risks of Jass type 1MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype (odds ratio [OR]: 2.14, 95% confidence interval [CI]: 1.46, 3.13; p-value = 9 × 10-5) and Jass type 2non-MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype CRC (OR: 2.20, 95% CI: 1.26, 3.86; p-value = 0.005). The magnitude of these associations was stronger compared with Jass type 4non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-wildtype CRC (p-differences: 0.03 and 0.04, respectively). A 1-SD (SD:13.4 cm) increment in waist circumference increased risk of Jass type 3non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-mutated (OR 1.73, 95% CI: 1.34, 2.25; p-value = 9 × 10-5) that was stronger compared with Jass type 4 CRC (p-difference: 0.03). A higher body fat percentage (SD:8.5%) increased risk of Jass type 1 CRC (OR: 2.59, 95% CI: 1.49, 4.48; p-value = 0.001), which was greater than Jass type 4 CRC (p-difference: 0.03).

INTERPRETATION: Body size was more strongly linked to the serrated (Jass types 1 and 2) and alternate (Jass type 3) pathways of colorectal carcinogenesis in comparison to the traditional pathway (Jass type 4).

FUNDING: Cancer Research UK, National Institute for Health Research, Medical Research Council, National Institutes of Health, National Cancer Institute, American Institute for Cancer Research, Brigham and Women's Hospital, Prevent Cancer Foundation, Victorian Cancer Agency, Swedish Research Council, Swedish Cancer Society, Region Västerbotten, Knut and Alice Wallenberg Foundation, Lion's Cancer Research Foundation, Insamlingsstiftelsen, Umeå University. Full funding details are provided in acknowledgements.

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